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Tulotta et al. J Cancer Metastasis Treat 2019;5:74 I http://dx.doi.org/10.20517/2394-4722.2019.022 Page 3 of 11

Figure 1. CXCL12-induced signalling via CXCR4 and CXCR7. (A) CXCL12 binds to CXCR4, inducing Gα and Gβγ dissociation and
activation of PI3K, MAPK, AC, and PLC signalling pathways. CXCL12 binding to CXCR4 activates β-Arrestin, leading to MAPK signalling
pathway activation or receptor internalization. (B) CXCR4 can form homo- and hetero-dimers with CXCR7. (C) CXCL12 binding to CXCR7
induces, via β-Arrestin, MAPK signalling activation, or CXCL12 scavenging, through receptor internalisation and recycling to the plasma
membrane. CXCL12-mediated signalling plays a role in cell chemotaxis, migration, proliferation and survival. PI3K: phosphatidylinositide
3-kinase; MAPK: mitogen-activated protein kinases; AC: adenyly cyclase; PLC: phospholipase C

[24]
[25]
[26]
(GBM) , Ewing sarcoma and leukemia . Elevated CXCR4 levels result in increased cell proliferation,
dedifferentiation, migration and metastatic spreading of tumour cells, cancer stem cell (CSC) maintenance
and it has been associated with the development of tumour resistance towards conventional therapies,
[27]
leading to poor patient prognosis .
CXCR4 is expressed by both cancer cells and surrounding stromal cells [Figure 2]. The recruitment of
stromal cells expressing CXCR4 can be guided by the secretion of CXCL12 by cancer cells themselves
[28]
or other stromal cells, such as MSCs and CAFs . Moreover, CXCL12 secreted by CAFs displays effects
[29]
on tumour cells, enhancing invasive potential and functioning as a protective shield against T cells,
[30]
boosting immune escaping mechanisms . In this context, pharmacological inhibition of CXCR4,
resulted in redistribution of CD3+ T cells within the “cancer cell nest”, as defined by the authors, causing
[31]
reduced cancer cell growth and improved response to check-point inhibitors . CXCR4 is involved
in leukocyte trafficking, hematopoietic stem progenitor cells homing and neutrophil retention in the
bone marrow during homeostasis, inflammation, infection and cancer [12,32-35] . Infiltration of CXCR4hi
neutrophils associates with faster tumour growth and angiogenesis in IFNβ deficient mice, injected with
[36]
melanoma and fibrosarcoma . CXCR4hi macrophages have been identified in CXCL12-enriched tumour